Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects the Veterans and the general population. Currently, there is no effective treatment and most patients die within 2 years after disease onset. One important neuropathology hallmark of ALS is the accumulation of misfolded proteins within the affected neurons, which progressively and irreversibly activate endoplasmic reticulum (ER) stress cell death mechanisms. Indeed, there is mounting evidence that ER stress is an important mechanism driving neurotoxicity in ALS. However, it is unclear how ER stress leads to apoptosis in ALS or whether this highly conserved mechanism can be harnessed to develop therapeutic targets that can improve the ability of neurons to reset the homeostasis of unfolded protein response (UPR), mitigate the disease progression, and prolong the survival in ALS patients. This new RR&D Merit Review proposal will develop small molecule chemicals that block ER stress-induced neurodegeneration in pre-clinical models of ALS. Our unpublished data support an important role of stress-activated protein kinase HIPK2 (homeodomain interacting protein kinase 2) in activating ER stress induced by chemical agents and in mouse model of neurodegeneration caused by mutant SOD1G93A protein. Interestingly, similar HIPK2 activation has also been identified in tissues from patients with familial and sporadic ALS. Together, these results provide proof-of-principle evidence that blocking HIPK2 can protect motor neurons neurodegeneration caused by misfolded mutant proteins in familial and sporadic ALS. If successful, our research will have profound impacts on the diagnosis, treatment, and rehabilitation of Veterans who suffer from ALS.